Genetic Polymorphism and Infectious Diseases in Indian Population

Abstract

Infectious diseases represent a major health problem worldwide, both in terms of morbidity and mortality. The development of an infectious disease results from complex interaction between the host, pathogen and the environment. Generally, genetics is not perceived to be influential in development of infectious diseases. However, increased understanding of molecular pathology has identified critical steps and molecular players involved in development and progression of infection. It is conceivable that any genetic variants of the molecules involved may influence the process of infectivity leading to variable susceptibility to infectious diseases and/or variable immune response. The same infectious agent may cause different immune responses in different individuals. In the majority of infectious diseases only a proportion of individuals exposed to a pathogen become infected and develops clinically evident disease. This heterogeneity and inter-individual variation in development of infectious disease and clinical outcomes is indicative to the role of genetics in modulating response to pathogen. Genetic polymorphism in candidate genes may influence the susceptibility/ resistance to infectious diseases directly or indirectly depending on its role in the pathogenesis. Tuberculosis, malaria and HIV are among the top leading infections in India and are considered emerging or re-emerging threats in India as well as most of the world. The objective of the present study was to examine the role of hosts’ genetic polymorphism in HIV, tuberculosis and malarial infections in Indian population and elucidating the functional association of genetic variability with these infectious diseases. The literature has already identified few genes involved in each of these infections; associated SNPs of these genes are studied in this report. However, we have realized that there may be several unreported genetic variants in Indian population and their roles cannot be ruled out in development of these infections. Therefore, it was thought prudent to sequence few of these genes from Indian samples and attempt to identify unreported novel variants and examine their roles in the disease process. For HIV, reported variants of chemokine receptor 5 (CCR5) and stromal derived factor-1 (SDF-1) genes were evaluated in Indian population. Similarly, variants of vitamin D receptor (VDR) and mannose binding lectin-2 (MBL-2) genes were selected for tuberculosis susceptibility studies. In case of P. falciparum malaria, intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor-α (TNF-α) were analysed. Frequencies of the selected genetic variants mentioned above were determined. The occurrence of these variants in Indian population was compared with the available ethnic data from other global populations. Significant correlation was observed for CCR5-59402 and CCR5-59356 variants in association with HIV-1 infection and development of AIDS. CCR5-59402A variant was found to be associated with protection to HIV-1 infection (p= 0.03). In case of CCR5-59356, C allele had association with increased risk to HIV-1 infection (p= 0.003) in Indian population. It indicates the distinct role of cis regulatory polymorphism in influencing CCR5 receptor expression and HIV-1 disease progression through the channel of differential transcriptional efficiencies. These results should be further validated in larger study cohorts of different regional ethnicity of Indian population to conclusively demonstrate the genotype phenotype correlation. The study also highlights the significance of understanding the effects of host genotype on development of innate and acquired immunity that would support the current approach to diagnosis and treatment. Infectious diseases susceptibility/ resistance is not determined by a single genetic factor, but it’s a complex interplay between multiple genetic and environmental factors, regulated by a range of different factors. The knowledge of frequency distribution of host genetic variants for establishing the risk profiles specific for Indian population could contribute to optimising future approaches for preventing the infection and long term disease management i.e. utilization of patient’s genetic makeup information in selection of therapies administered. Thus, study can prove to be useful in revealing valuable insights into the pathogenesis of infectious diseases and advocate novel strategies for therapeutic intervention.